Phenotypic heterogeneity in small cell lung cancer. Abstract. Small cell lung cancer (SCLC) constitutes a group of malignancies responsible for the about 24,000 cancer deaths every year in the United States. Little progress has been made in decreasing SCLC mortality. Gene expression and mutation profiling efforts to identify driver mutations, gene amplifications, or signatures with clinical utility in SCLC have been limited and thus far been unfruitful. Our preliminary data point towards the existence of subclasses of SCLCs and new therapeutic targets. Based on these preliminary data we hypothesize that discovering the temporality, frequency and nature of primary and secondary mutations associated with tumor progression, the characterization of a small number of subpopulations and their responses to drugs will lead to significant improvements in the diagnosis, prognosis, and treatment of lung cancer. We propose to validate the two distinct phenotypes- neuroendocrine and mesenchymal- of SCLC within primary tumors. We will investigate the heterogeneity of the tumors based on fresh specimens by single cell mass Cytometry as it relates to their behavior. Our single cell analysis will inform us on the clonality of the lesions and intra-tumor heterogeneity. We will determine the temporality of events in tumorigenesis of SCLC in primary tumors and in tumors resisting chemotherapy. Whole genome sequencing and RNAseq analyses will be performed on these samples to assay tumor heterogeneity and compare before and after treatment as well as to identify changes specific to exceptional responders. Finally, we will interrogate in patient derive xenografts tumor heterogeneity in SCLCs who relapse after chemotherapy to discover new pathway activation and test new strategies for intervention including SYK and EPHA2 tyrosine kinase inhibitors. The ultimate goal of this translational research is to develop personalized management for patients presenting with SCLC. Phenotypic heterogeneity among cancer cells, observed even within single tumors, presents enormous challenges for developing optimal targeted treatment plans. We hope to uncover SCLC heterogeneity and its implications for chemotherapy. We hope to identify driver mutations and mutations that are uniquely associated with tumor progression, including therapy induced mutations. This will better inform the design of clinical trials and assist clinicians in tailoring treatment in individual patients.